Cataract is the most common cause of blindness in the world today. Surgery is generally very effective in restoring sight;however, a common complication is the development of posterior capsule opacification. This is caused by aberrant growth and differentiation of lens cells. One way to prevent this costly complication is to promote normal patterns of lens cell growth and differentiation. In relation to fiber differentiation, evidence indicates that members of the Wnt growth factor family, through activation of the Wnt/planar cell polarity (PCP) signaling pathway, provide a critical component of a FGF- induced signaling cascade that is required for fiber differentiation. This project will test the hypothesis that Wnt/PCP signaling plays a critical role in directing the elongation, migration and alignment of lens fibers. In Part (a), investigations by RT-PCR, in situ hybridisation, immunolocalization and Western blotting, will determine expression patterns of members of the core Wnt/PCP signaling families, prickle, van gogh-like and scribble, during lens development. Part (b) will then manipulate expression of PCP signaling components in lens epithelial explants and in transgenic mice to determine their functional roles in fiber differentiation. Using siRNA, dominant-negative and conditional knockout strategies the functions of the PCP signaling components (identified in a) in promoting the elongation, directed migration and alignment of lens fibers, will be tested. These studies will provide vital new information about mechanisms and molecules that are required to promote the growth, differentiation and maintenance of lens cells and in so doing will address key objectives identified within the 'Lens and Cataract Program'of NEI. PUBLIC HEALTH RELEVANCE With approximately 20 million people affected, clouding of the lens (cataract) is the most common cause of blindness in the world today. Although surgery can initially be very effective in restoring sight, in the longer term complications are common and often result in the development of a secondary cataract. A central aim in our laboratory is to devise molecular strategies that (i) prevent the aberrant lens cell behaviour that occurs after surgery and (ii) promote normal patterns of lens cell growth and differentiation so that lens clarity is maintained.